Abstract 300: Mangiferin Conjugated Gold Nanoparticles Protect Against The Development Of Abdominal Aortic Aneurysm In Apoe–/– Mouse Model

Abstract

Objective: There are no drugs to prevent the growth of abdominal aortic aneurysm (AAA), responsible for ~200,000 deaths in the world each year. There is a growing interest in natural anti-inflammatory compounds using nanotechnology-based drug-delivery. Mangiferin (MGF) is one such phytochemical isolated from Mangifera indica. Conjugation of MGF on gold nanoparticles (MGF-AuNPs) enhances bioavailability, through cellular penetration, presenting new opportunities toward the design of innovative nanomedicine agents. Recently, we have demonstrated the unique applications of MGF-AuNPs as an immunomodulatory therapeutic agent in the treatment of metastatic breast and prostate cancers. Here, we investigated whether MGF-AuNPs prevent the development of AAA. Approach and Results: Apoe –/– mice were subjected to angiotensin (AngII; 1μg/min/kg)-induced AAA. MGF-AuNPs (~7 mg/30g mouse) or starch (S)-AuNPs were administered daily, a week prior to AngII and continued for 28 days (n=6-12 per group). The incidences of AAA were significantly attenuated with MGF-AuNPs than AngII group (P<0.001), associated with a decrease in maximal intra-luminal diameter (P<0.001), pulse wave velocity (P<0.001), distensibility (P<0.05) and radial strain (P<0.05). Degradation of elastin (P<0.001), pro-inflammatory cytokines (P<0.01) and apoptotic cell death (P<0.01) were significantly reduced in the aortae of MGF-AuNPs treated Apoe –/– mice than AngII group. Mechanistically, Notch1, its ligands (Jag1, Dll4) and downstream targets (HeyL, NFκB2, pStat3), were significantly reduced by MGF-AuNPs in the aorta (P<0.01) than AngII group. In the macrophages overexpressed with activated Notch1 (NICD), MGF-AuNPs significantly diminished the expression of Jag1 (P<0.001), HeyL (P<0.001), Il6 (P<0.001) and NFκB2 (P<0.001). MGF-AuNPs also prevented the nuclear translocation of NICD and its downstream effector pStat3, in the macrophages transfected with NICD plasmid. Conclusion: Our studies provide compelling pre-clinical evidence of protective effects of MGF-AuNPs on AAA development through inactivation of Notch1 signaling, thus present realistic potential toward clinical translation of this nanoceutical for use as a non-invasive effective treatment for AAA.